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EP2852594B1 - Derives de pyrimidino[1,2-c]quinazolinone en tant qu'inhibiteurs de tyrosine kinases - Google Patents

Derives de pyrimidino[1,2-c]quinazolinone en tant qu'inhibiteurs de tyrosine kinases Download PDF

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Publication number
EP2852594B1
EP2852594B1 EP13726968.4A EP13726968A EP2852594B1 EP 2852594 B1 EP2852594 B1 EP 2852594B1 EP 13726968 A EP13726968 A EP 13726968A EP 2852594 B1 EP2852594 B1 EP 2852594B1
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Prior art keywords
phenyl
pyrimido
tetrahydro
oxo
quinazolin
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EP2852594A1 (fr
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Thomas C. Malone
Julie A. Wurster
Clarence Eugene Hull, Iii
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Allergan Inc
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Allergan Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction.
  • the present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
  • PTKs Protein tyrosine kinases
  • receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment).
  • ligand specific growth factor
  • ligand dimerization transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation.
  • Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment).
  • tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • SH2 serosine kinases
  • Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue.
  • Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • the receptor-type tyrosine kinases comprise a large family of transmembrane receptors with diverse biological activities.
  • the intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses.
  • the non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. A more detailed discussion of receptor and non-receptor tyrosine kinases is provided in Cowan-Jacob Cell Mol. Life Sci., 2996, 63, 2608-2625 .
  • RTK kinases have been found to be involved in cellular signaling pathways leading to pathological conditions, including exudative age-related macular degeneration ( Ni et al. Opthalmologica 2009 223 401-410 ; Chappelow et al. Drugs 2008 68 1029-1036 ), diabetic retinopathy ( Zhang et al., Int. J. Biochem. Cell Biol. 2009 41 2368-2371 ), cancer ( Aora et al. J. Path. Exp. Ther. 2006, 315, 971 ), psoriasis ( Heidenreich et al Drug News Perspective 2008 21 97-105 ), rosacea ( Smith, J. R., V. B.
  • VEGFR and PDGFR ⁇ may provide a greater therapeutic effect in by causing regression of existing neovascular blood vessels present in the disease ( Adamis et al., Am. J. Pathol. 2006 168 2036-2053 ).
  • cancer inhibition of multiple RTK signaling pathways has been suggested to have a greater effect than inhibiting a single RTK pathway ( DePinho et al., Science 2007 318 287-290 ; Bergers et al. J. Clin Invest. 2003 111 1287-1295 ).
  • the international patent application WO99/45009 discloses heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors.
  • the present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction by blocking the VEGF and/or PDGF receptors.
  • Such compounds are useful for the treatment of diseases related to unregulated tyrosine kinase signal transduction, including vascular proliferative disorders such as diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity.
  • the compounds of the present invention have the following general formula I: Wherein
  • a is 0.
  • n is 0 or 1.
  • n 0.
  • Ar is a carbocyclic aryl
  • Ar is phenyl
  • Ar 1 is selected from the group consisting of phenyl, furanyl and halo, lower alkyl, lower alkyloxy, lower alkylthio and halo-loweralkyl-substituted phenyl and furanyl.
  • Ar 1 is selected from the group consisting of phenyl, furanyl and methyl, methoxy, methylthio, bromo, fluoro, trifluoro and chloro- substituted phenyl and furanyl.
  • Ar 1 is selected from the group consisting of fluoro and trifluoro-substituted phenyl.
  • R is hydrogen or acetate.
  • R is hydrogen, i.e. n is 0.
  • R 5 and R 6 are hydrogen and/or methyl; more preferably at least one of R 5 and R 6 is hydrogen.
  • said compound has an IC 50 value for compound inhibition in the VEGFR2 Kinase Assay of less then 1000 nM.
  • said compound has an IC 50 value for compound inhibition in the VEGFR2 Kinase Assay of less than 500 nM.
  • the compound of the present invention is a 4-aryl-substituted- (2H)-pyrimido [1,2-c]quinazoline-6-oxo, or a pharmaceutically acceptable salt thereof, wherein said 4-aryl is substituted with a carboamino, or an aminocarbo or an aminocarboamino aryl group and wherein said compound binds to a tyrosine kinase receptor (such as a VEGF or a PDGF receptor).
  • a tyrosine kinase receptor such as a VEGF or a PDGF receptor
  • the 4-aryl-substituted- (2H)-pyrimido [1,2-c]quinazoline-6-oxo compound is phenyl- substituted- (2H)-pyrimido [1,2-c]quinazoline-6-oxo.
  • the carboamino, aminocarbo or aminocarboamino aryl group a carboamino, aminocarbo or aminocarboamino phenyl group.
  • Compounds of formula I are useful as kinase inhibitors. As such, compounds of formula I will be useful for treating diseases related to unregulated tyrosine kinase signal transduction, for example, cancer, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases.
  • the compounds of the present invention are useful for treatment of mesangial cell proliferative disorders and metabolic diseases, pterigium, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, rosacea, diabetis mellitus, wound healing, inflammation and neurodegenerative diseases and preferably ophthalmic diseases, i.e. diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, etc.
  • the present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of one or more of the above-described compounds and a pharmaceutically acceptable carrier or excipient, wherein said compositions are effective for treating the above diseases and conditions; especially ophthalmic diseases and conditions.
  • Such a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
  • compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, rosacea, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as exudative age related macular degeneration and diabetic retinopathy
  • diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, rosacea, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as exudative age related macular degeneration and diabetic retinopathy
  • Hydrocarbyl refers to a hydrocarbon radical having only carbon and hydrogen atoms.
  • the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
  • Substituted hydrocarbyl refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halo, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, dialkylamino, hydroxyl, phosphate, thiol, etc.
  • “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutically acceptable salts may also refer to those salts which retain the biological effectiveness and properties of the free acid and which are obtained by reaction with inorganic bases such as sodium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide or by organic bases such as tromethamine, choline, diethylamine and lysine and the like.
  • Alkyl refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
  • Alkoxy refers to O-alkyl.
  • Alkoxycarbonyl refers to -C(O)O-alkyl or -C(O)O-aryl.
  • Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
  • the aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
  • Carbocyclic aryl refers to an aryl group wherein the ring atoms are carbon.
  • Heteroaryl or “heterocyclic aryl” refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
  • the compounds of this invention may be prepared by the general reaction schemes set forth below.
  • the compounds of the present invention are selected from the compounds of Table 1, below.
  • Table 1 Example Number Structure Compound Name 1 3-(4-chlorophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one 2 3-(3-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one 3 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[3-(6-oxo-3,4,6,7-tetrahydro-2H-pyrimido [1,2-c]quinazolin-3-yl)phenyl]urea 4 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido [1,2-c]quinazolin-6-one 5 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(6-o
  • Biochemical KDR kinase assays were performed in 96 well microliter plates that were coated overnight with 75 ⁇ g/well of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates were washed with 2 mLs per well PBS + 0.05% Tween-20 (PBS-T), blocked by incubation with PBS containing 1% BSA, then washed with 2 mLs per well PBS-T prior to starting the reaction.
  • PBS Phosphate Buffered Saline
  • Reactions were carried out in 100 ⁇ L reaction volumes containing 2.7 ⁇ M ATP in kinase buffer (50mM Hepes buffer pH 7.4, 20mM MgCl 2 , 0.1 mM MnCl 2 and 0.2 mM Na 3 VO 4 ).
  • Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%.
  • Reactions were initiated by the addition 20 ul per well of kinase buffer containing 200-300 ng purified cytoplasmic domain KDR protein (BPS Bioscience, San Diego, CA). Following a 15 minute incubation at 30° C, the reactions were washed 2 mLs per well PBS-T.
  • IC 50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
  • TABLE 2 Example Number Structure VEGFR2 Enzyme IC 50 (micromolar) 1 >10 2 >10 3 0.76 4 >10 5 0.36 6 4.75 7 0.34 8 1.8 9 0.25 10 0.33 11 4.03 12 >10 13 1.47 14 >10 15 6.38 16 >10 17 >10 18 >10 19 >10 20 >10 21 >10 22 >10 23 >10 24 1.5 25 0.39
  • Methyl 3-amino-4-formylbenzoate was prepared by the method described in J. Amer. Chem. Soc. 2008, 130, 416-417 . The title compound was obtained as a yellow solid (197 mg, 46%).
  • reaction was heated at 60 °C for 23 hours, then added a small spatula tip of 3-methyl-furan-2-carboxylic acid and BOP plus 0.015 mL N, N-diisopropylethylamine and continued heating at 80 °C for an additional 4 hours.
  • the reaction mixture was partitioned between EtOAc and aqueous Na 2 CO 3 solution, the EtOAc layer washed with H 2 O, brine, dried with anhydrous Na 2 SO 4 and evaporated.
  • the resulting yellow oil was chromatographed on a prep plate eluting with 20% MeOH/CHCl 3 plus NH 4 OH.
  • reaction mixture was filtered through a celite pad (27 g), rinsing with methanol (760 mL). The filtrate and rinse were concentrated to dryness in vacuo to give the crude title compound as red-brown gum (24 g, 96% yield). This material was used without further purification.
  • reaction mixture was washed sequentially with water (100 mL), 10 wt% aqueous orthophosphoric acid (2 x 75 mL) and water (75 mL).
  • the separated organic layer was dried over anhydrous magnesium sulfate (12 g), filtered, and concentrated to dryness under reduced pressure to afford the title compound as an oily brown material (48 g, quantitatative).
  • the batch was then stirred at 80 °C for at least 5 h or until HPLC analysis showed that the reaction had proceeded to greater the 98% completion.
  • the cooled reaction mixture was filtered through a celite pad (8.8 g) and the filter cake was rinsed with MeOH (110 mL).
  • the filtrate and rinse were diluted with toluene (90 mL) and concentrated to dryness under reduced pressure.
  • the residue was stirred with aqueous 20 wt% sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature. This mixture was extracted with CH 2 Cl 2 (2 x 180 mL) and the separated organic layers were concentrated to dryness in vacuo .
  • the concentrate (20 g) was dissolved with methanol (10 mL) and loaded onto a Biotage KP-Sil SNAP cartridge (100 g) that had been pre-equilibrated with 300 mL 5% v/v triethylamine in hexane.
  • a Biotage unit was used to elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure as quickly as possible to provide the title compound as a yellow solid (2.9 g 23% yield).
  • the batch was quenched with cooling by drop-wise addition of methanol (46 mL), followed by a solution of 12.1 N aqueous hydrochloric acid (97 g, 82.1 mL, 1.00 mol) in water (138 mL) over at least 30 min.
  • Batch temperature was held at 20-35 °C during quench; an exotherm and effervescence were observed during the quench.
  • the mixture was stirred at 50 °C for at least 1 h and concentrated under reduced pressure to a volume of ⁇ 230 mL (to remove tetrahydrofuran).
  • the concentrate was diluted with water (453 mL) and extracted with ethyl acetate (2 x 453 mL).
  • the concentrate (20 g) was dissolved with methanol (20 mL) and loaded onto a KP-Sil samplet (34 g). The sample was allowed to dry before loading it into a Biotage KP-Sil SNAP cartridge (340 g). A Biotage unit was used to elute the cartridge with a ethyl acetate-hexane gradient (0% to 90%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure to provide the title compound as a yellow solid (1.6 g, 13% yield).
  • novel compounds of this invention include any compound which is a 4-aryl-substituted- (2H)-pyrimido [1,2-c]quinazoline-6-oxo, e.g. a substituted 4-phenyl-substituted- (2H)-pyrimido [1,2-c]quinazoline-6-oxo, wherein said 4-aryl, e.g.
  • said 4-phenyl is substituted with a carboamino, or an aminocarbo or an aminocarboamino aryl group and binds to a tyrosine kinase receptor, e.g. a VEGF and/or PDGF receptor.
  • said 4- aryl e.g. said 4-phenyl, is linked to said carboamino, aminocarbo or aminocarboamino aryl by a linking group represented by the formula -(NR 5 ) p -C(O)-(NR 6 ) q -wherein p is 0 or 1 and q is 0 or 1 and R 5 and R 6 are as defined above.

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Claims (14)

  1. Composé représenté par la formule I :
    Figure imgb0108
     ou un de sels pharmaceutiquement acceptables, dans lequel :
    Ar est un groupement aryle ;
    Ar1 est un groupement aryle ;
    X est :
    Figure imgb0109
    R est sélectionné dans le groupe constitué par un groupement alkyle inférieur, OC(O)R4, (CR1R2)aC(O)OR3, (CR1R2)aOR3, (CR1R2)aN(R4)C(O)R3, (CR1R2)aC(O)N(R3)2, (CR1R2)aN(R4)C(O)OR3, (CR1R2)aN(R4)C(O)N(R3)2, (CR1R2)aN(R3)2, où N(R3)2 peut former un noyau hétérocyclique éventuellemnt substitué par un ou plusieurs parmi un halogène et un alkyle inférieur ;
    R1, R2 et R4 sont indépendamment sélectionnés dans le groupe constitué par l'hydrogène, un halogène et un alkyle inférieur ;
    R3 est sélectionné dans le groupe constitué par l'hydrogène et un alkyle inférieur ;
    R5 est sélectionné parmi l'hydrogène et un alkyle inférieur ;
    R6 est sélectionné parmi l'hydrogène et un alkyle inférieur ;
    a est 0 ou un entier de 1 à 4 ; et
    n est 0 ou un entier de 1 à 4, le terme alkyle inférieur faisant référence à un groupement alkyle de 1 à 7 atomes de carbone.
  2. Composé selon la revendication 1, dans lequel Ar est un aryle carboxylique ; de préférence dans lequel Ar est un phényle.
  3. Composé selon la revendication 1, dans lequel Ar1 est sélectionné dans le groupe constitué de groupements phényle, furanyle et phényle et furanyle substitués par un halogène, un alkyle inférieur, un alkyloxy inférieur, un alkylthio inférieur et un halo-alkyle inférieur ; de préférence dans lequel Ar1 est sélectionné dans le groupe constitué de groupements phényle, furanyle et phényle et furanyle substitués par un méthyle, un méthoxy, un méthylthio, un bromo, un fluoro, un trifluoro et un chloro.
  4. Composé selon la revendication 3, dans lequel Ar1 est sélectionné dans le groupe constitué du groupement phényle substitué par un fluoro et un trifluoro.
  5. Composé selon la revendication 1, dans lequel R est sélectionné dans le groupe constitué par l'hydrogène et un acétate.
  6. Composé selon la revendication 1, dans lequel a est 0.
  7. Composé selon la revendication 1, dans lequel n est 0 ou 1 ; de préférence dans lequel n est 0.
  8. Composé selon la revendication 1 sélectionné dans le groupe constitué par :
    1-[2-fluoro-5-(trifluorométhyl)phényl]-3-[3-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)-phényl]urée,
    1-[2-fluoro-5-(trifluorométhyl)phényl]-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)-phényl]urée ,
    1-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]-quinazolin-3-yl)phényl]urée,
    1-[4-chloro-3-(trifluorométhyl)phényl]-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)-phényl]urée,
    1-[3-(méthylthio)phényl]-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée,
    1-(3-bromophényl)-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée,
    1-3-(méthylphényl)-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée,
    1-(4-(méthylphényl)-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée,
    1-(4-(méthoxyphényl)-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée,
    1-(3-(méthoxylphényl)-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée,
    3-méthyl-N-[3-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]-2-furamide,
    3-méthyl-N-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]-2-furamide,
    N-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c] quinazolin-3-yl)phényl]-3-(trifluorométhyl)benzamide, et
    méthyl 3-{4-[({[(2-fluoro-5-trifluorométhyl)phényl]-amino}carbonyl)(méthyl)amino]phényl}-6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-9-carboxylate ;
    1-[3-méthyl-4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]-3-(3-méthylphényl)urée ; et
    1-[2-fluoro-5-(trifluorométhyl)phényl]-3-[3-méthyl-4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée ; ou un de leurs sels pharmaceutiquement acceptables.
  9. Composé selon la revendication 8 sélectionné dans le groupe constitué par :
    1-[2-fluoro-5-(trifluorométhyl)phényl]-3-[3-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)-phényl]urée,
    1-[2-fluoro-5-(trifluorométhyl)phényl]-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)-phényl]urée ,
    1-[4-chloro-3-(trifluorométhyl)phényl]-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)-phényl]urée,
    1-(3-bromophényl)-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée,
    1-3-(méthylphényl)-3-[4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée et
    3-méthyl-N-[3-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]-2-furamide ; et
    1-[2-fluoro-5-(trifluorométhyl)phényl]-3-[3-méthyl-4-(6-oxo-3,4,6,7-tétrahydro-2H-pyrimido[1,2-c]quinazolin-3-yl)phényl]urée ; ou un de leurs sels pharmaceutiquement acceptables.
  10. Composé qui est un 4-aryl-substitué-(2H-pyrimido[1,2-c]quinazoline-6-oxo, ou un de ses sels pharmaceutiquement acceptables, dans lequel ledit 4-aryle est substitué par un groupement carboamino ou aminocarbo ou aminocarboamino aryle tel que défini dans la revendication 1 pour utilisation en tant qu'inhibiteur de récepteur de tyrosine-kinase.
  11. Composition pharmaceutique comprenant au moins un composé selon la revendication 1, ou un de ses sels pharmaceutiquement acceptables, et au moins un vecteur ou excipient pharmaceutiquement acceptable.
  12. Composé selon la revendication 1 destiné à être utilisé dans un procédé de traitement d'une maladie liée à la transduction du signal de tyrosine-kinase non régulée, le procédé comprenant l'étape consistant à administrer à un sujet qui en a besoin une quantité thérapeutiquement efficace d'au moins un composé selon la revendication 1, ou un de ses sels pharmaceutiquement acceptables, dans lequel ladite maladie est sélectionnée dans le groupe constitué du cancer, des troubles prolifératifs des vaisseaux sanguins, des troubles fibrotiques, des troubles prolifératifs des cellules mésangiales et des maladies métaboliques.
  13. Composé destiné à une utilisation selon la revendication 12, dans lequel le trouble prolifératif des vaisseaux sanguins est sélectionné dans le groupe constitué de la la rénitopathie diabétique, de la dégénérescence maculaire liée à l'âge exsudative, de la rétinopathie du prématuré, du pterygium, de l'acné rosacée, de l'arthrite et du resténose ; le trouble fibrotique est sélectionné dans le groupe constitué de la cirrhose hépatique et de l'athérosclérose ; le trouble prolifératif des cellules mésangiales est sélectionné dans le groupe constitué de la glomérulonéphrite, de la néphropathie diabétique, de la néphrosclérose maligne, des syndromes de microangiopathie thrombotique, du rejet de greffe et des glomérulopathies ; et la maladie métabolique est sélectionnée dans le groupe constitué du psoriasis, du diabète sucré, de la cicatrisation des plaies, de l'inflammation et des maladies neurodégénératives.
  14. Composé pour utilisation selon la revendication 13, dans lequel ladite maladie proliférative des vaisseaux sanguins est une maladie ophtalmologique sélectionnée dans le groupe constitué de la rétinopathie diabétique, de la dégénérescence maculaire liée à l'âge exsudative et de la rétinopathie du prématuré.
EP13726968.4A 2012-05-21 2013-05-20 Derives de pyrimidino[1,2-c]quinazolinone en tant qu'inhibiteurs de tyrosine kinases Active EP2852594B1 (fr)

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US201261649516P 2012-05-21 2012-05-21
PCT/US2013/041846 WO2013177053A1 (fr) 2012-05-21 2013-05-20 Dérivés de pyrimidino[1,2-c]quinazolinone en tant qu'inhibiteurs de tyrosine kinase

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WO2020048827A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés de la 1,3,9-triazaspiro[5.5]undécan-2-one
WO2020048828A1 (fr) 2018-09-03 2020-03-12 Bayer Pharma Aktiengesellschaft Composés du 5-hétéroaryl-3,9-diazaspiro[5.5]undécane

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DE3046366A1 (de) * 1980-12-09 1982-07-08 Bayer Ag, 5090 Leverkusen Tricyclische cytosinderivate zur verwendung in arzneimitteln und verfahren zu ihrer herstellung
EP1066286B1 (fr) * 1998-03-04 2009-04-29 Bristol-Myers Squibb Company Inhibiteurs de la proteine tyrosine kinase, a base d'imidazopyrazine a substitution heterocyclo

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US20130310394A1 (en) 2013-11-21
WO2013177053A1 (fr) 2013-11-28
US9365575B2 (en) 2016-06-14

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